Atraumatic Splenic Rupture Unveiling Mumps With an Underlying B-cell Lymphoid Hyperplasia: A Diagnostic Conundrum.

Atraumatic splenic rupture (ASR) is an unfamiliar entity that is potentially life-threatening if there is a delay in the diagnosis. Due to its rarity and its non-specific presentation, it can be a challenge to diagnose early. In this report, we present a case of a 42-year-old male patient who presented to the emergency department with nonspecific abdominal pain and had no past medical history. The patient presented abdominal pain associated with nausea, vomiting, and sweating. On examination, the patient was found to be tachycardic and mildly hypotensive, with mild left upper quadrant tenderness, and a lactate of 4 mmol/L on venous blood gas analysis. He was urgently transferred to the resuscitation area, where resuscitation commenced. Further investigations revealed significant anemia. The contrast-enhanced CT of the abdomen performed revealed a 13-cm splenic hemostasis suggestive of non-traumatic splenic rupture. The patient lacked any history of blunt trauma or family history that could account for the splenic rupture. The patient was taken to the theatre by the surgical team as he remained unstable. He received four units of blood in the theatre and underwent splenectomy due to the spleen being unsalvageable. Post-operatively, the patient was admitted to the high-dependency unit (HDU) for close monitoring. Histological examination of the splenic tissue revealed B-cell lymphoid hyperplasia and negative PCR for clonality. The patient was found to be IgG-positive for mumps and was not vaccinated for MMR. Surgeons believe it is the main cause of ASR, given that little literature available establishes the same. The case highlights the importance of consideration of ASR in patients presenting with unexplained abdominal pain and hemodynamic instability, even without evidence of trauma. Early imaging and operative intervention are lifesaving. The histologic findings indicate that there may be an associated hemopoietic disorder, and this case highlights the need for clinicians to consider splenic involvement in patients with mumps who present with abdominal pain or signs of hemodynamic instability.

Phylogenetic and recombination analysis of Begomoviruses associated with Cotton leaf curl disease and in silico analysis of viral-host protein interactions.

Cotton leaf curl disease (CLCuD), caused by numerous begomoviruses (BGVs), is a highly disastrous disease in cotton crops worldwide. To date, several efforts have shown limited success in controlling this disease. CLCuD-associated BGVs (CABs) are known for their high rate of intra and interspecific recombinations, which raises an urgent need to find an efficient and conserved target region to combat disease. In the present study, phylogenetic analysis of selected 11 CABs, along with associated alphasatellites, and betasatellites revealed a close evolutionary relationship among them. Recombination analysis of 1374 isolates of CABs revealed 54 recombination events for the major players of CLCuD in cotton and the Cotton leaf curl Multan virus (CLCuMuV) as the most recombinant CAB. Recombination breakpoints were frequent in all regions except C2 and C3. C3-encoded protein, known as viral replication enhancer (REn), promotes viral replication by enhancing the activity of replicase (Rep) protein. Both proteins were found to contain significantly conserved domains and motifs. The identified motifs were found crucial for their interaction with host protein PCNA (Proliferating cell nuclear antigen), facilitating viral replication. Interruption at the REn-PCNA and Rep-PCNA interactions by targeting the identified conserved motifs is proposed as a prospect to halt viral replication, after suitable experimental validation.

Material-level countermeasures for securing microfluidic biochips.

Flow-based microfluidic biochips (FMBs) have been rapidly commercialized and deployed in recent years for biological computing, clinical diagnostics, and point-of-care-tests (POCTs). However, outsourcing FMBs makes them susceptible to material-level attacks by malicious actors for illegitimate monetary gain. The attacks involve deliberate material degradation of an FMB's polydimethylsiloxane (PDMS) components by either doping with reactive solvents or altering the PDMS curing ratio during fabrication. Such attacks are stealthy enough to evade detection and deteriorate the FMB's function. Furthermore, material-level attacks can become prevalent in attacks based on intellectual property (IP) theft, such as counterfeiting, overbuilding, etc., which involve unscrupulous third-party manufacturers. To address this problem, we present a dynamic material-level watermarking scheme for PDMS-based FMBs with microvalves using a perylene-labeled fluorescent dye. The dyed microvalves show a unique excimer intensity peak under 405 nm laser excitation. Moreover, when pneumatically actuated, the peak shows a predetermined downward shift in intensity as a function of mechanical strain. We validated this protection scheme experimentally using fluorescence microscopy, which showed a high correlation (R2 = 0.971) between the normalized excimer intensity change and the maximum principal strain of the actuated microvalves. To detect curing ratio-based attacks, we adapted machine learning (ML) models, which were trained on the force-displacement data obtained from a mechanical punch test method. Our ML models achieved more than 99% accuracy in detecting curing ratio anomalies. These countermeasures can be used to proactively safeguard FMBs against material-level attacks in the era of global pandemics and diagnostics based on POCTs.

Reduced intestinal lipid absorption improves glucose metabolism in aged G2-Terc knockout mice.

BACKGROUND: Biological aging is an important factor leading to the development of pathologies associated with metabolic dysregulation, including type 2 diabetes, cancer, cardiovascular and neurodegenerative diseases. Telomere length, a central feature of aging, has additionally been identified as inversely associated with glucose tolerance and the development of type 2 diabetes. However, the effects of shortened telomeres on body weight and metabolism remain incompletely understood. Here, we studied the metabolic consequences of moderate telomere shortening using second generation loss of telomerase activity in mice. RESULTS: Aged male and female G2 Terc-/- mice and controls were characterized with respect to body weight and composition, glucose homeostasis, insulin sensitivity and metabolic activity. This was complemented with molecular and histological analysis of adipose tissue, liver and the intestine as well as microbiota analysis. We show that moderate telomere shortening leads to improved insulin sensitivity and glucose tolerance in aged male and female G2 Terc-/- mice. This is accompanied by reduced fat and lean mass in both sexes. Mechanistically, the metabolic improvement results from reduced dietary lipid uptake in the intestine, characterized by reduced gene expression of fatty acid transporters in enterocytes of the small intestine. Furthermore, G2-Terc-/- mice showed significant alterations in the composition of gut microbiota, potentially contributing to the improved glucose metabolism. CONCLUSIONS: Our study shows that moderate telomere shortening reduces intestinal lipid absorption, resulting in reduced adiposity and improved glucose metabolism in aged mice. These findings will guide future murine and human aging studies and provide important insights into the age associated development of type 2 diabetes and metabolic syndrome.

Epidemiology, treatment patterns, and disease burden of cytomegalovirus in hematopoietic cell transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America. METHODS: The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011-17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden. RESULTS: Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%-61.2% (23 studies) and 2.9%-15.7% (10 studies), respectively. Recurrence occurred in 19.8%-37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%-10% of recipients (five studies). Patient-reported outcomes and economic data were scarce. CONCLUSION: The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.

Comparative expression analysis of water buffalo (Bubalus bubalis) to identify genes associated with economically important traits.

The milk, meat, skins, and draft power of domestic water buffalo (Bubalus bubalis) provide substantial contributions to the global agricultural economy. The world's water buffalo population is primarily found in Asia, and the buffalo supports more people per capita than any other livestock species. For evaluating the workflow, output rate, and completeness of transcriptome assemblies within and between reference-free (RF) de novo transcriptome and reference-based (RB) datasets, abundant bioinformatics studies have been carried out to date. However, comprehensive documentation of the degree of consistency and variability of the data produced by comparing gene expression levels using these two separate techniques is lacking. In the present study, we assessed the variations in the number of differentially expressed genes (DEGs) attained with RF and RB approaches. In light of this, we conducted a study to identify, annotate, and analyze the genes associated with four economically important traits of buffalo, viz., milk volume, age at first calving, post-partum cyclicity, and feed conversion efficiency. A total of 14,201 and 279 DEGs were identified in RF and RB assemblies. Gene ontology (GO) terms associated with the identified genes were allocated to traits under study. Identified genes improve the knowledge of the underlying mechanism of trait expression in water buffalo which may support improved breeding plans for higher productivity. The empirical findings of this study using RNA-seq data-based assembly may improve the understanding of genetic diversity in relation to buffalo productivity and provide important contributions to answer biological issues regarding the transcriptome of non-model organisms.

Epidemiology, management, and burden of cytomegalovirus in solid organ transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) is a frequent infectious complication following solid organ transplantation (SOT). Considering significant differences in healthcare systems, a systematic review was conducted to describe the epidemiology, management, and burden of CMV post-SOT in selected countries outside of Europe and North America. METHODS: MEDLINE, Embase, and Cochrane databases were searched for observational studies in SOT recipients across 15 countries in the regions of Asia, Pacific, and Latin America (search period: January 1, 2011 to September 17, 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatment patterns and guidelines, refractory and/or resistant CMV, patient-reported outcomes, and economic burden. RESULTS: Of 2708 studies identified, 49 were eligible (n = 43/49; 87.8% in adults; n = 34/49, 69.4% in kidney recipients). Across studies, selection of CMV preventive strategy was based on CMV serostatus. Overall, rates of CMV infection (within 1 year) and CMV disease post-SOT were respectively, 10.3%-63.2% (9 studies) and 0%-19.0% (17 studies). Recurrence occurred in 35.4%-41.0% cases (3 studies) and up to 5.3% recipients died of CMV-associated causes (11 studies). Conventional treatments for CMV infection/disease included ganciclovir (GCV) or valganciclovir. Up to 4.4% patients were resistant to treatment (3 studies); no studies reported on refractory CMV. Treatment-related adverse events with GCV included neutropenia (2%-29%), anemia (13%-48%), leukopenia (11%-37%), and thrombocytopenia (13%-24%). Data on economic burden were scarce. CONCLUSION: Outside of North America and Europe, rates of CMV infection/disease post-SOT are highly variable and CMV recurrence is frequent. CMV resistance and treatment-associated adverse events, including myelosuppression, highlight unmet needs with conventional therapy.

The rising threat of geminiviruses: molecular insights into the disease mechanism and mitigation strategies.

BACKGROUND: Geminiviruses are among the most threatening emerging plant viruses, accountable for a huge loss to agricultural production worldwide. These viruses have been responsible for some serious outbreaks during the last few decades across different parts of the world. Sincere efforts have been made to regulate the disease incidence by incorporating a multi-dimensional approach, and this process has been facilitated greatly by the advent of molecular techniques. But, the mixed infection due to the polyphagous nature of vectors results in viral recombination followed by the emergence of novel viral strains which thus renders the existing mitigation strategies ineffective. Hence, a multifaceted insight into the molecular mechanism of the disease is really needed to understand the regulatory points; much has been done in this direction during the last few years. The present review aims to explore all the latest developments made so far and to organize the information in a comprehensive manner so that some novel hypotheses for controlling the disease may be generated. METHODS AND RESULTS: Starting with the background information, diverse genera of geminiviruses are listed along with their pathological and economic impacts. A comprehensive and detailed mechanism of infection is elaborated to study the interactions between vector, host, and virus at different stages in the life cycle of geminiviruses. Finally, an effort isalso made to analyze the progress made at the molecular level for the development of various mitigation strategies and suggest more effective and better approaches for controlling the disease. CONCLUSION: The study has provided a thorough understanding of molecular mechanism of geminivirus infection.

Association of Elevated Body Mass Index and Outcomes of Arthroscopic Treatment for Osteochondral Lesions of the Talus.

Background: Osteochondral lesions of the talus (OLTs) are a common condition found in patients with chronic ankle pain after previous ankle sprains. Surgical management is indicated after conservative management has failed. Hypothesis/Purpose: This study evaluates the influence of body mass index (BMI) on the early clinical outcomes of arthroscopic debridement and microfracture of OLTs. Methods: A total of 252 patients with symptomatic OLTs who failed conservative management underwent arthroscopic debridement and microfracture of OLTs over the affected ankle between 2007 and 2017. Patients from this cohort were divided into 2 groups based on BMI: the normal BMI group (NB Group) (BMI 18.5-25.0) and overweight and obese BMI group (OB Group) (BMI ≥25). Visual analogue scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score, and the physical and mental component summaries of the 36-Item Short-Form Health Survey (PCS and MCS, respectively) were prospectively collected from the cohort during their standard postoperative outpatient follow-up. Results: The NB Group (n=105) and OB Group (n=147) were well matched demographically. The operative duration was significantly shorter for the NB Group compared to the OB Group. Patients from both groups had significant improvements in VAS, AOFAS, and PCS scores postoperatively at 6 and 24 months after surgery (P < .05). Between both groups, patients had comparable VAS, AOFAS, and PCS scores at preoperation, 6 months postoperation, and 24 months postoperation (P > .05). However, MCS in the OB Group was lower at 24 months postoperatively compared with the NB Group (P < .05). The OB Group reported better satisfaction scores (82.4% vs 72.6%, P < .05), and a greater proportion had their expectations met (88.2% vs 77.9%, P < .05). Conclusion: A BMI ≥25 was not associated with worse postoperative pain and functional outcomes, but rather was found to be associated with greater satisfaction and fulfillment. However, patients with BMI ≥25 required longer procedure duration and had poorer MCS scores at 24 months after surgery.Level of Evidence: Level III, retrospective cohort study.

Radiofrequency Plantar Fascia Coblation With and Without Gastrocnemius Recession in the Management of Recalcitrant Plantar Fasciitis.

BACKGROUND: Plantar fasciitis is the most common cause of plantar heel pain. Although most are self-limiting, recalcitrant conditions can be debilitating, significantly reducing patient's quality of life. A myriad of surgical procedures are available for the treatment of recalcitrant plantar fasciitis (RPF) with little consensus on best practice. This purpose of this study was to assess the efficacy of radiofrequency coblation with and without gastrocnemius release on the surgical management of RPF. METHODS: Between June 2013 and June 2019, a total of 128 patients with RPF and tight gastrocnemius were treated surgically. Presence of tight gastrocnemius was assessed clinically by a positive Silfverskiold test. Group A (n = 73) consisted of patients who underwent radiofrequency coblation alone; group B (n = 55) consisted of patients who underwent radiofrequency coblation and endoscopic gastrocnemius recession. The primary outcome measure was visual analog scale (VAS) score. Secondary outcome measures included (1) American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score; (2) physical (PCS) and mental component summaries (MCS) of the 36-Item Short Form Health Survey; (3) overall assessment of improvement, expectation fulfilment, and satisfaction; and (4) complication rates. RESULTS: Both groups reported significant improvement in VAS, AOFAS, and PCS scores postoperatively at 6 and 24 months. Group B (radiofrequency coblation with gastrocnemius recession) was associated with better VAS at both 6 months (3.0 ± 2.9 vs 1.7 ± 2.6, P < .05) and 24 months postoperatively (1.9 ± 3.1 vs 0.8 ± 2.0, P < .05) compared with group A (radiofrequency coblation without gastrocnemius recession). At 24 months postoperatively, no differences were found in AOFAS, PCS, MCS scores, expectation fulfilment, or overall satisfaction. No wound complications were reported in either group. One patient (group B) has persistent symptoms consistent with tarsal tunnel syndrome. CONCLUSION: In this retrospective cohort comparative study, treatment of RPF with radiofrequency coblation alone was associated with slightly inferior results than radiofrequency coblation combined with endoscopic gastrocnemius recession in terms of pain relief without an increase in complication rates. However, at 2 years, we did not find a significant difference in other measures of outcome. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

PAT2 regulates vATPase assembly and lysosomal acidification in brown adipocytes.

OBJECTIVE: Brown adipocytes play a key role in maintaining body temperature as well as glucose and lipid homeostasis. However, brown adipocytes need to adapt their thermogenic activity and substrate utilization to changes in nutrient availability. Amongst the multiple factors influencing brown adipocyte activity, autophagy is an important regulatory element of thermogenic capacity and activity. Nevertheless, a specific sensing mechanism of extracellular amino acid availability linking autophagy to nutrient availability in brown adipocytes is unknown. METHODS: To characterize the role of the amino acid transporter PAT2/SLC36A2 in brown adipocytes, loss or gain of function of PAT2 were studied with respect to differentiation, subcellular localization, lysosomal activity and autophagy. Activity of vATPase was evaluated by quenching of EGFP fused to LC3 or FITC-dextran loaded lysosomes in brown adipocytes upon amino acid starvation, whereas the effect of PAT2 on assembly of the vATPase was investigated by Native-PAGE. RESULTS: We show that PAT2 translocates from the plasma membrane to the lysosome in response to amino acid withdrawal. Loss or overexpression of PAT2 impair lysosomal acidification and starvation-induced S6K re-phosphorylation, as PAT2 facilitates the assembly of the lysosomal vATPase, by recruitment of the cytoplasmic V1 subunit to the lysosome. CONCLUSIONS: PAT2 is an important sensor of extracellular amino acids and regulator of lysosomal acidification in brown adipocytes.

Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of a Romiplostim Biosimilar in Chronic Refractory Immune Thrombocytopenic Purpura (ITP) Patients.

Romiplostim (Nplate®, Amgen Inc.) is an orphan drug approved for the treatment of chronic refractory immune thrombolytic purpura (ITP) in adult and pediatric patients. Limited availability of pharmacokinetic (PK) data and large inter- and intra-subject variability in PK and platelet response is a challenge in the clinical development of a romiplostim biosimilar. We compared pharmacokinetics (PK), pharmacodynamics (PD)/efficacy, and safety of a romiplostim biosimilar with Nplate in 24 patients with ITP following a single 3 µg/kg dose, and assessed efficacy of the romiplostim biosimilar at a titrated dose range of 1-5 µg/kg in 50 patients with ITP. The PK of the romiplostim biosimilar did not differ compared to the PK of Nplate, and PD/efficacy responses were similar between the products following the single dose. The romiplostim biosimilar showed historically comparable PD/efficacy with Nplate over 8 weeks when treated at the titrated dose range. It was well tolerated in both the studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12288-021-01431-y.

Mid-Term Functional and Radiological Outcomes of Total Ankle Replacement in an Asian Cohort.

There are limited studies looking at longer-term outcomes of the total ankle replacement (TAR) in the Asian cohort. Asian ankles are smaller in size and are more varus compared to Western cohorts. Cultural differences also require increased ankle range of motion demands. Therefore, assessment of longer-term functional and radiological outcomes in the Asian cohort is warranted. Between 2007 and 2015, 43 consecutive patients received a 3-component, cementless, unconstrained, fully congruent TAR. Patients were followed up over a mean 8 (range 5-14 years). Preoperative and postoperative AOFAS ankle-hindfoot score (AOFAS-AHS), visual analogue score (VAS), physical and mental component scores of the SF-36 (PCS and MCS respectively) were calculated. European Foot and Ankle Score was also recorded at 8 years. Radiographs were reviewed postoperatively to assess implant position and study evidence of implant loosening and impingement. At 8 years, survivorship was 83.5%. Reasons for implant removal included infection (n = 2) and aseptic loosening (n = 5). AOFAS-AHS, VAS MCS at 8 years postoperatively were comparable to outcomes at 2 years postoperatively (p > .05). PCS at 8 years demonstrated improvement compared to 2 years postoperatively (49 ± 7 vs 42 ± 11, p = .048). Radiographic impingement was noted in 9 cases (20.9%). Radiological loosening was noted in 8 cases with 5 cases requiring revision surgery. At 8 years postoperatively, clinical outcomes, radiological outcomes and survivorship following TAR in an Asian cohort are satisfactory and comparable to that found in existing literature. Long-term studies are required to ascertain survivorship of TAR. Implant design with the Asian cohort in mind may yield improved outcomes.

Denosumab biosimilar in postmenopausal osteoporotic women: A randomized, assessor-blind, active-controlled clinical trial.

OBJECTIVE: The study assessed the efficacy, safety, pharmacokinetic (PK), and immunogenicity profiles of denosumab-biosimilar and denosumab-reference in postmenopausal osteoporotic women from India. MATERIALS AND METHODS: In this randomized, assessor-blind, active-control, multicenter trial, 114 patients were randomly allocated to receive denosumab-biosimilar (n = 58) or denosumab-reference (n = 56) at a subcutaneous dose of 60 mg every 6 months, for a year. Vitamin D and oral calcium were given daily. Lumbar spine bone mineral density (BMD) change was the primary end point. RESULTS: Of 114 randomized patients, 111 (denosumab-biosimilar, n = 56; denosumab-reference, n = 55) completed the study. All 114 patients were part of safety and immunogenicity analyses, 110 (denosumab-biosimilar, n = 56; denosumab-reference, n = 54) were part of efficacy analysis, and 20 (denosumab-biosimilar, n = 10; denosumab-reference, n = 10) were part of PK analysis. The bone mineral density (BMD) (lumbar spine) percent change at 1 year with denosumab-biosimilar and denosumab-reference (7.22 vs. 7.62; difference:-0.40; 95% confidence interval: -5.92, 5.12) showed no statistically relevant difference. Likewise, alkaline phosphatase (bone-specific) and PK parameters also did not show statistically relevant differences. Adverse events were reported in 44.83% of patients on denosumab-biosimilar versus 33.93% of patients on denosumab-reference; most events were mild or moderate and not related to the study drugs. No patients showed anti-denosumab antibody positivity. CONCLUSIONS: Denosumab-biosimilar and denosumab-reference showed biosimilarity in osteoporotic postmenopausal women. Availability of denosumab-biosimilar provides a treatment alternative for patients.

Single-Dose Pharmacokinetics, Pharmacodynamics and Immunogenicity, and Multiple-Dose Immunogenicity of INTP5 (Pegfilgrastim Biosimilar) Versus Reference Pegfilgrastim in Healthy Subjects.

BACKGROUND AND OBJECTIVE: INTP5 has been developed as a pegfilgrastim biosimilar. Single-dose, crossover study compared the pharmacokinetics and pharmacodynamics (PK/PD) of INTP5 (pegfilgrastim biosimilar) with reference pegfilgrastim (Neulasta®, pegfilgrastim-ref) and a multiple-dose, parallel-group study compared the immunogenicity of INTP5 with pegfilgrastim-ref in healthy subjects as part of a complete clinical development plan. METHODS: In the PK/PD study, subjects received a single subcutaneous 6 mg dose of INTP5 and pegfilgrastim-ref (N = 142) separated by a 6-week washout period. The primary endpoints were area under the serum concentration-time curve measured from time zero to infinity (AUC0-∞) and maximum measured serum concentration (Cmax) of pegfilgrastim and area under the absolute neutrophil count (ANC) versus time curve from time zero to t (AUEC0-t) and maximum measured ANC (Emax) of baseline non-adjusted ANCs. In the immunogenicity study, subjects received two 6 mg doses of INTP5 (N = 100) or pegfilgrastim-ref (N = 100) separated by 21 days. The primary endpoints were incidence of anti-drug antibodies (ADAs) in the two treatment groups. RESULTS: The primary PK endpoints [AUC0-∞ (90% CI 108.59-123.11) and Cmax (106.24-118.99)] and the primary PD endpoints [AUEC0-t (99.07-102.32) and Emax (100.24-104.25)] met the acceptance criteria of 80-125%. The incidence of ADAs was 10.6% in the INTP5 arm and 9.0% in the pegfilgrastim-ref arm. The 90% CI for risk difference of the ADA incidence between INTP5 and pegfilgrastim-ref was 1.64% (- 5.40 to 8.68) and was within the 10% margin. No neutralizing antibodies were reported. Immunogenicity did not impact PK/PD parameters and subjects with aberrant PK/PD/safety did not show immunogenicity concerns. Incidence of adverse events (AEs) was similar with INTP5 and pegfilgrastim-ref in both studies. The most common AEs were musculoskeletal pain and headache. CONCLUSION: INTP5 showed PK/PD equivalence with pegfilgrastim-ref following a single dose, no clinically meaningful difference in the immune response following multiple doses, and a comparable safety profile.

Lateral column osteotomy versus subtalar arthroereisis in the correction of Grade IIB adult acquired flatfoot deformity: A clinical and radiological follow-up at 24 months.

BACKGROUND: Adult acquired flat foot deformity (AAFD) is a spectrum of conditions which can be progressive if untreated. Surgical correction and restoration of anatomical relationship are often required in the treatment of symptomatic Grade II AAFD after a failed course of conservative treatment. There is a paucity of literature recommending best practice-especially in the adult population. The authors aim to compare radiological and clinical outcomes of two widely employed surgical techniques in the treatment of symptomatic AAFD. METHODS: A retrospective study of 76 patients with Grade IIB AAFD and had undergone either lateral column lengthening (LCL) or subtalar arthroereisis (STA) surgical correction of their symptomatic AAFD. Each technique was augmented with both bony osteotomy and soft tissue transfer as determined by on table assessment. Clinical and radiological outcomes were reviewed 24 months after surgery. RESULTS: LCL and STA groups had comparable radiological outcomes at 24 months after surgery. However, LCL group demonstrated superior American Orthopaedic Foot and Ankle Society (AOFAS) midfoot (90.3 ± 12.6 vs 81.1 ± 20.6, p < 0.001) as well as Visual Analogue Scale (VAS) midfoot scores (0.5 ± 1.6 vs 1.3 ± 2.4, p < 0.001) at 24 months compared to the STA group. STA had a higher complication rate (20.6% vs 4.4%), with all cases complaining of sinus tarsi pain requiring subsequent removal of implant. CONCLUSION: There is a role for either techniques in the treatment of symptomatic AAFD. LCL whilst more invasive has demonstrated superior outcome scores and lower complication rates at 24 months compared to STA. Patients need to be counselled appropriately to appreciate the benefits of each technique.

Comparative study for intermediate crystal size of NaI(Tl) scintillation detector.

The distinctive features of a well-known NaI(Tl) scintillation detector, by virtue of its crystal size, are experimentally investigated by observing changes in parameters such as intrinsic efficiency (εi), photo-peak efficiency (εp), resolution, and response function to incident gamma photon energy. This study provides a better understanding for the choice of crystal size of the scintillation detector in Compton scattering experiments. The response function of the NaI(Tl) detector is in the form of an inverse matrix focusing on the retort of the crystal when gamma photons are incident upon it. The response function of the NaI(Tl) detector depends upon the distance between the source and the detector, composition of the material for the crystal itself, photo-fraction, solid angle, incident gamma energy, and geometry of the experimental setup. The factors responsible for broadening of full energy and backscattered peaks are discussed for present investigations. The observed results indicate that the resolution of the detector varies with the incident energy of gamma radiation, and it also depends upon the size of the crystal of the detector. Statistical fluctuations related with the scintillation mechanism are found to be responsible for broadening of instrumental line width (photo-peak). The signal-to-noise ratio and photo-fraction for different crystal sizes of the scintillation detector corrected for efficiency of the detector are also discussed.

A randomized, double-blind, parallel-group, single­dose, pharmacokinetic bioequivalence study of INTP24 and bevacizumab in healthy adult men.

PURPOSE: To demonstrate pharmacokinetic (PK) equivalence and to compare safety of INTP24 (bevacizumab biosimilar) with that of US-bevacizumab and EU-bevacizumab in healthy male subjects. METHODS: In this randomized, parallel-group, double-blind study, male subjects were randomized (1:1:1) to receive a single 1 mg/kg intravenous infusion of either INTP24, US-bevacizumab, or EU-bevacizumab. The primary endpoint was area under serum concentration (AUC) from time zero to infinity (AUC0-∞). Secondary endpoints were AUC from time zero to last quantifiable concentration (AUC0-t), maximum concentration (Cmax), other PK parameters, immunogenicity, and safety. RESULTS: A total of 117 subjects (39/group) were dosed; 113 subjects (37, 37, and 39 in INPT24, US-bevacizumab, and EU-bevacizumab groups, respectively) completed the study and were included in the PK analysis. Baseline demographics were similar across the three groups. The 90% confidence intervals (CI) of geometric mean ratios (GMR) of ln-transformed AUC0-∞ and Cmax of INTP24 relative to US-bevacizumab and EU-bevacizumab were within the acceptance range of 80%-125% (INTP24 vs. US-bevacizumab, 96.55-112.51% and 99.16-112.79%: INTP24 vs. EU-bevacizumab, 94.84-110.17% and 96.32-109.28%). The 90% CIs of GMRs for AUC0-t was also within 80-125% for INTP24 vs. US-bevacizumab and INTP24 vs. EU-bevacizumab. Safety and immunogenicity profiles were similar across the three groups. Twenty-one (17.95%) subjects experienced at least one AE and 9 (7.69%) were ADA positive. One treatment-related serious adverse event (varicella zoster infection) was reported in INTP24 group. CONCLUSION: This study demonstrated PK bioequivalence of INTP24 to US-bevacizumab and EU-bevacizumab in healthy male subjects and showed similar safety and immunogenicity profiles across the treatment groups.

Identification and characterization of trait-specific SNPs using ddRAD sequencing in water buffalo.

Single Nucleotide Polymorphism (SNP) is one of the important molecular markers widely used in animal breeding program for improvement of any desirable genetic traits. Considering this, the present study was carried out to identify, annotate and analyze the SNPs related to four important traits of buffalo viz. milk volume, age at first calving, post-partum cyclicity and feed conversion efficiency. We identified 246,495, 168,202, 74,136 and 194,747 genome-wide SNPs related to mentioned traits, respectively using ddRAD sequencing technique based on 85 samples of Murrah Buffaloes. Distribution of these SNPs were highest (61.69%) and lowest (1.78%) in intron and exon regions, respectively. Under coding regions, the SNPs for the four traits were further classified as synonymous (4697) and non-synonymous (3827). Moreover, Gene Ontology (GO) terms of identified genes assigned to various traits. These characterized SNPs will enhance the knowledge of cellular mechanism for enhancing productivity of water buffalo through molecular breeding.

Shape Similarity by Fractal Dimensionality: An Application in the de novo Design of (-)-Englerin A Mimetics.

Molecular shape and pharmacological function are interconnected. To capture shape, the fractal dimensionality concept was employed, providing a natural similarity measure for the virtual screening of de novo generated small molecules mimicking the structurally complex natural product (-)-englerin A. Two of the top-ranking designs were synthesized and tested for their ability to modulate transient receptor potential (TRP) cation channels which are cellular targets of (-)-englerin A. Intracellular calcium assays and electrophysiological whole-cell measurements of TRPC4 and TRPM8 channels revealed potent inhibitory effects of one of the computer-generated compounds. Four derivatives of this identified hit compound had comparable effects on TRPC4 and TRPM8. The results of this study corroborate the use of fractal dimensionality as an innovative shape-based molecular representation for molecular scaffold-hopping.